Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
Sandra and Edward Meyer Cancer Center, New York, NY, USA.
Immunol Rev. 2017 Nov;280(1):220-230. doi: 10.1111/imr.12568.
Ionizing irradiation has been extensively employed for the clinical management of solid tumors, with therapeutic or palliative intents, for decades. Until recently, radiation therapy (RT) was believed to mediate antineoplastic activity mostly (if not only) as a consequence of cancer cell-intrinsic effects. Indeed, the macromolecular damage imposed to malignant cells by RT initiates one or multiple signal transduction cascades that drive a permanent proliferative arrest (cellular senescence) or regulated cell death. Both these phenomena show a rather linear dose-response correlation. However, RT also mediates consistent immunological activity, not only as an "on-target effect" originating within irradiated cancer cells, but also as an "off-target effect" depending on the interaction between RT and stromal, endothelial, and immune components of the tumor microenvironment. Interestingly, the immunological activity of RT does not exhibit linear dose-response correlation. Here, we discuss the mechanisms whereby RT alters the capacity of the immune system to recognize and eliminate irradiated cancer cells, either as an "on-target" or as on "off-target" effect. In particular, we discuss the antagonism between the immunostimulatory and immunosuppressive effects of RT as we delineate combinatorial strategies to boost the former at the expenses of the latter.
几十年来，电离辐射已被广泛用于实体瘤的临床治疗，具有治疗或姑息的目的。直到最近，放射治疗（RT）被认为主要（如果不是唯一的话）通过癌细胞内在效应来介导抗肿瘤活性。事实上，RT 对恶性细胞造成的大分子损伤引发了一个或多个信号转导级联反应，导致永久性增殖停滞（细胞衰老）或受调控的细胞死亡。这两种现象都显示出相当线性的剂量反应相关性。然而，RT 还介导一致的免疫活性，不仅作为源自受照射癌细胞的“靶向内效应”，而且作为取决于 RT 与肿瘤微环境的基质、内皮和免疫成分之间相互作用的“靶向外效应”。有趣的是，RT 的免疫活性不表现出线性剂量反应相关性。在这里，我们讨论了 RT 改变免疫系统识别和消除受照射癌细胞的能力的机制，无论是作为“靶向内”还是“靶向外”效应。特别是，我们讨论了 RT 的免疫刺激和免疫抑制作用之间的拮抗作用，同时我们描述了以牺牲后者为代价来增强前者的组合策略。
